KR20120080239A - Method for treating herpes virus infection - Google Patents

Abstract

The present invention provides herpes virus activity in a patient by administering to a patient in need thereof an active ingredient consisting essentially of an effective amount of diclofenac (eg, 3-7% w / w) or a pharmaceutically acceptable salt thereof It is about how to inhibit.

Description

How to treat herpes virus infection {METHOD FOR TREATING HERPES VIRUS INFECTION}

The present invention relates to a method of inhibiting herpes virus activity in a patient by administering to a patient in need thereof an active ingredient consisting essentially of an effective amount of diclofenac or a pharmaceutically acceptable salt thereof.

Herpes viruses include a large family of double stranded DNA viruses. The herpes virus family can be divided into three subfamilies based on host range and flexibility, viral life cycle, and numerous biological properties such as virus persistence and latency (ie, α, β, and γ). 8 types of herpes viruses (simple herpes virus types 1 and 2 (HSV-1 and HSV-2), varicella zoster virus (VZV), human cytomegalovirus (HCMV), Ephstein-Barr virus (EBV), and Human herpes viruses 6, 7 and 8 (HHV-6, HHV-7 and HHV-8)) have been shown to infect humans.

Among the herpes viruses, two commonly known viruses are simple herpes virus types 1 and 2 (referred to as HSV1 and HSV2) and varicella zoster virus (VZV). HSV1 causes oral facial lesions, commonly known as herpes simplex or herpes zoster. These lesions are most commonly seen on the lips, but can appear on the mucous lines of the face, mouth, eyes and nose, and sometimes on the trunk of the hand. Infection of the mouth is designated by the term herpes labialis (also referred to as lip herpes). In addition, other parts of the face can be affected and its infection is referred to as simple facial herpes. Infections can also manifest themselves in other parts of the body. Approximately 30% of the US population suffers from recurrent episodes of HSV1. HSV2, which is less common than HSV1, causes genital lesions. Conversely, genital herpes (about 30% of cases) is caused by HSV1.

Varicella zoster virus (VZV) causes chickenpox (commonly known as chicken pox) and shingles (commonly known as shingle). Shingles affects the skin and nerves, which are characterized by small groups of blisters or lesions that appear along specific nerve segments. Lesions most often appear on the back, which can progress to the pain in the affected area.

Once an individual is infected with the herpes virus, the virus will later lie in the body. In the latent state, the virus is located in nerve cell bodies in the ganglion. Due to certain stimuli such as influenza infections, other respiratory disorders, gastrointestinal tract infections, stress, fatigue, menstruation, pregnancy, allergies, sunlight or heat, the latent virus can be activated and skin from the ganglion along well-defined nerve pathways They migrate to the surface, multiply there and cause symptoms.

Acyclovir (chemical name, acycloguanosine) is a guanosine analog antiviral drug that targets a virally encoded DNA polymerase. Acyclovir is used primarily in the treatment of herpes zoster (shingles) as well as in the treatment of herpes simplex virus infections. Acyclovir is used to reduce pain and increase the rate of treatment of ulcers or blisters in people with the first or recurrent onset of chickenpox (chicken fox), shingles and genital herpes. Acyclovir is a class of antiviral agents called so-called synthetic nucleoside analogs. This works by preventing the herpes virus from spreading in the body. Acyclovir will not cure genital herpes, which will not prevent genital herpes from spreading to others. Acyclovir is poorly soluble in water and exhibits low bioavailability. Relatively long recovery times are required (ie, generally it takes more than two weeks for the patient to recover) and the high prescription costs make the drug appear less attractive to the patient.

Lidocaine (2- (diethylamino) -N- (2,6-dimethylphenyl) -acetamide, local anesthetic) is known for the treatment of ventricular tachycardia (arrhythmia of the heart) as an intravenous injection solution. In addition, lidocaine is widely used as a blood constrictor for topical application or locally to reduce blood flow in aerosols (eg, nasal aerosols reduce nasal congestion). Lidocaine is also known for its therapeutic effect in reducing shingles (herpes zoster and post-herpes neuralgia) and post-herpes neuralgia (PHN) neuronal impairment from similar neural pathways.

Lidocaine base is free oil soluble. Insoluble in water and therefore not suitable for use in aqueous suspensions, ethanol is required to obtain a liquid solution. However, its salt form (lidocaine-HCl) is very soluble in water and alcohol. Thus, lidocaine-HCl is generally the form used for the preparation of injection solutions.

Diclofenac, which is 2- (2,6-dichloroanilino) -phenyl-acetic acid, is known for its role as an anti-rheumatic agent for treating rheumatoid arthritis. Diclofenac belongs to the acetic acid class of NSAIDs (nonsteroidal anti-inflammatory drugs). Diclofenac is taken to reduce inflammation and is taken as an analgesic to reduce pain in conditions such as arthritis or acute injury. Due to their relatively low solubility in water, aqueous solutions of diclofenac are difficult to achieve.

There is still a need for effective methods of treating herpes virus infections and inhibiting viral activity. This method does not use multiple drugs and has minimal side effects.

Summary of the Invention

The present invention relates to a method of inhibiting herpes virus activity in a patient. The method comprises topically administering to a patient in need thereof an active ingredient consisting essentially of an effective amount of diclofenac or a pharmaceutically acceptable salt thereof. This alias requires only one single active compound (ie diclofenac) to treat herpes virus infection. The method does not require the use of multiple drugs.

The present invention is suitable for inhibiting the activity of herpes virus, including herpes simplex virus type 1 (HSV-1), herpes simplex virus type-2, varicella zoster virus, and combinations thereof.

1 shows the inhibitory effect on lesion number, lesion area and viral titer by (a) 5% lidofenac and 5% acyclovir, (b) 5% acyclovir, and (c) 5% lidofenac Indicates.
2 compares the inhibitory effect on virus titers by lidofenac (1%, 3%, and 5%), diclofenac (5%), lidocaine (5%), and acyclovir (5%).

The inventors have found an effective method of inhibiting herpes virus activity. The inventors have found that, as an active compound, diclofenac or a pharmaceutically acceptable salt thereof alone is sufficient to reduce herpes virus titer when tested in animals with anti-herpes virus effects. In order to inhibit herpes virus activity, no additional active compound such as acyclovir or lidocaine is required. By using a single drug, the method minimizes the side effects caused by multiple drugs, improves patient compliance and provides economic benefits.

The present invention relates to a method of inhibiting herpes virus activity in a patient. The method includes: identifying a patient suffering from a herpes virus infection, and topically administering to the patient an active ingredient consisting essentially of an effective amount of diclofenac or a pharmaceutically acceptable salt thereof Viral activity is inhibited).

As used herein, a “pharmaceutically acceptable salt” is a salt that retains the desired biological activity of the parent compound while not conferring an unwanted toxic effect. Pharmaceutically acceptable salts may be formed with metals or organic counterions, including alkali metal salts such as sodium or potassium; Alkaline earth metal salts such as magnesium or calcium; And ammonium salts of ammonium or tetra-alkyl (i.e., NX ₄ + (wherein, X is C _{1 -. 4} include, Im), and the like "pharmaceutically acceptable salts" as used herein is a salt form, As another active compound.

As used herein, “effective amount” refers to an amount effective to inhibit and reduce viral activity. Viral activity can be measured by viral titer, lesion number and / or lesion area. The effective amount of diclofenac is about 1-10%, preferably 2-8%, or 3-7%, or 4-6%.

The method inhibits the activity of the herpes virus, including herpes simplex virus type 1 (HSV-1), herpes simplex virus type-2, varicella zoster virus, and combinations thereof.

The method topically administers an effective amount of Diclofenac or a salt thereof to the area where the patient complains of pain. Preferred diclofenac is diclofenac sodium or diclofenac potassium, more preferably diclofenac sodium. The effective amount of diclofenac is about 1-10%, preferably 2-8%, 3-8%, 3-7%, or 4-6% (w / w). For example, the effective amount of diclofenac is about 5% (w / w). The painful area is typically the external tissue of the patient. After diclofenac treatment, total lesion number, lesion size and viral titer are reduced.

As used herein, “about” refers to ± 10% of the recited values.

The present invention also provides a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and the active compound Diclofenac or a pharmaceutically acceptable salt thereof. Generally, the active compound or pharmaceutically acceptable salt thereof in the pharmaceutical composition is about 1-10%, or 2-8%, or 3-8%, or 3-7%, or 4-6% (w / w ) For example, the active compound in the pharmaceutical composition is about 1, 3, or 5%.

Pharmaceutically acceptable carriers can be selected by those skilled in the art using conventional criteria. Pharmaceutically acceptable carriers include, but are not limited to, non-aqueous base solutions, suspensions, emulsions, microemulsions, colloidal solution, gels and ointments. In addition, pharmaceutically acceptable carriers include saline and aqueous electrolyte solutions; Ionic and nonionic osmotic agents such as sodium chloride, potassium chloride, glycerol and dextrose; pH adjusting agents and buffers such as salts of hydroxides, hydronium phosphate, citrate, acetate and borate; Antioxidants such as bisulfite, sulfite, metabisulfite, thiosulfite, ascorbic acid, acetyl cysteine, cysteine, glutathione, butylated hydroxyanisol, butylated hydroxytoluene, tocopherol, and ascorbyl palmi Salts, acids and / or bases of tate; Surfactants such as lecithin, phospholipids (including but not limited to phosphatidylcholine, phosphatidylethanolamine and phosphatidyl inositiol); Poloxamers and poloxamines, polysorbates such as polysorbate 80, polysorbate 60, and polysorbate 20, polyethers such as polyethylene glycol and polypropylene glycol; Polyvinyls such as polyvinyl alcohol and povidone; Cellulose derivatives such as methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose and hydroxypropyl methylcellulose and salts thereof; Petroleum derivatives such as mineral oil and white petrolatum; Fats such as lanolin, peanut oil, palm oil, soybean oil; Mono-, di- and triglycerides; Polymers of acrylic acid such as carboxypolymethylene gels and polysaccharides such as dextran, and glycosaminoglycans such as sodium hyaluronate. Such pharmaceutically acceptable carriers can be preserved against bacterial contamination using well known preservatives, including benzalkonium chloride, ethylene diamine tetraacetic acid and salts thereof, benzetonium chloride, chlorexidine, chlorobutanol , Methylparaben, thimerosal and phenylethyl alcohol, including but not limited to, can be formulated as unpreserved formulations for single or multiple use.

Topical formulations comprising the active compound may be in the form of gels, creams, lotions, liquids, emulsions, ointments, sprays, solutions and suspensions.

In one embodiment, the active compound is incorporated into any acceptable carrier including liquids, creams, gels, lotions or another type of suspension that can be delivered to the area affected by topical application. In another embodiment, the pharmaceutical composition may be in dosage form such as tablets, capsules, granules, microgranules, powders, syrups, suppositories, injections and the like. The pharmaceutical composition may be prepared by conventional methods.

The pharmaceutical compositions of the present invention may be applied by any acceptable mode of systemic administration, including topical, oral, parenteral (such as intravenous, intramuscular, transdermal or rectal) and other systemic routes of administration. The active compound first reaches plasma and then disperses into the target tissue. Administration of the composition can vary based on the extent of infection and the individual response of each patient. Topical administration is the preferred route of administration for the present invention.

In a preferred embodiment, the composition is applied or rubbed topically over the affected area. The composition is applied topically at least once or twice per day, or three to five times per day. Generally, the topical composition is about 1-10%, preferably about 2-6%, 2-10%, 3-7%, 3-8%, 3-10%, 4-6%, 4 of the active compound -7%, or 4-8% (w / w). For example, the topical composition comprises about 3% or 5% (w / w) of the active compound. Depending on the area affected, typically 0.01-10 g, preferably 0.05-5 g, of topical composition is applied separately per dose. In general, the active compounds are applied topically separately at 1-500 mg, and preferably at 2.5-250 mg / dose. For example, 0.05 g of 5% dichlorophenac sodium (2.5 mg) per cm 2 of lesion area is applied. The active compound passes through the skin and is delivered to the area of discomfort.

Those skilled in the art will recognize a wide variety of delivery mechanisms suitable for the present invention.

The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention to the specific procedures described below.

Example

Example 1 Preparation of a Cream Formulation

Cream vehicle = [active ingredient] was prepared according to the following steps:

1. Preparation of oil phase: The mixing tube was submerged in a hot water bath (80 ± 2 ° C.). [Acyclovir, 50 g] Methyl paraben (1 g), propyl paraben (1 g), cetyl alcohol (60 g), sorbitan monostearate 60 (12 g), stearic acid (20 g), synthetic spermaceti (50 g), dimethyl Polysiloxane (30 g) and Miglyol 812 (70 g) were added to the mixing tube and stirred to mix well. The mixture was filtered once through 150 mesh to remove particles.

2. Preparation of Aqueous Phase: Another mixing tube was submerged in a high temperature water bath (80 ± 2 ° C.). [Diclofenac Sodium Salt, 50g] [Diclofenac Acid Lidocaine Salt, 10g, 30g, or 50g] Polysorbate 60 (36g), Propylene Glycol (160g), Sodium Citrate (10g), and Sufficient Purified Water (total Weight of 1000g ) Was added to the mixing tube and stirred until completely dissolved. The mixture was filtered once through 150 mesh to remove particles.

3. Emulsification: The oil phase was transferred to a steam-jacketed tank with a vacuum pressure of 35-40 mmHg. The aqueous phase was slowly added to the steam-jacket tank at a constant stirring rate using Homo-Mixer (25-35 Hz) for 25 minutes.

4. The emulsion of the previous step was cooled to a temperature of 30 ° C. under slow stirring to obtain a topical formulation in the dosage form of the cream.

Example 2. Different Compound Tests in Animals

purpose:

(1) ADO-1, ADO-2, ADO-3, and ADO-4; (2) 1% VDO99 cream, 3% VDO99 cream, 5% VDO99 cream and placebo thereof; (3) Effects of VGO99 Cream (Diclofenac Sodium, 50mg (RA009)), VDO99 Cream (Diclofenacic Acid, Lidocaine Salt 50mg (RA052)), VAO99 Cream (Lidocaine, 50mg (RA001)) and its Placebo Cream in Herpes Animal Model Tested. Cream formulation ± active ingredient was prepared according to Example 1.

Compounds Tested:

Group I

ADO-1: 5% acyclovir (50 mg / g) + 5% diclofenac acid lidocaine salt (lidofenac 50 mg / g)

ADO-2: 5% acyclovir (50 mg / g)

ADO-3: 5% Diclofenac Acid Lidocaine Salt (Lidofenac 50mg / g)

ADO-4: Vehicle.

Group II

1% VDO99 Cream: Diclofenac Acid, Lidocaine Salt (Lidofenac 10mg / g, RA032);

VDO99 Placebo Cream (RA035 Placebo);

3% VDO99 Cream: Diclofenac Acid, Lidocaine Salt (Lidofenac 30mg / g, RA033);

VDO99 Placebo Cream (RA036 Placebo);

5% VDO99 Cream: Diclofenac Acid, Lidocaine Salt (Lidofenac 50mg / g, RA034);

VDO99 Placebo Cream (RA037 Placebo).

Group III

1% VDO99 Cream: Diclofenac Acid, Lidocaine Salt (Lidofenac 10mg / g, RA032);

VDO99 Placebo Cream (RA035 Placebo);

3% VDO99 Cream: Diclofenac Acid, Lidocaine Salt (Lidofenac 30mg / g, RA033);

VDO99 Placebo Cream (RA036 Placebo);

5% VGO 99 Cream, Diclofenac Sodium, 50 mg / g (RA009), Placebo Cream (RA010);

5% VDO 99 Cream, Diclofenac Acid, Lidocaine Salt (Lidofenac 50mg / g, RA052), Placebo Cream (RA053);

5% VAO99 Cream, Lidocaine, 50 mg / g (RA001), Placebo Cream (RA003).

When not in use, the compound was kept in the dark at room temperature. 5% ACV / PEG (Zovirax Ointment) was used as a control in the experiment.

Animal inoculation

Hartley crossbreeding albino guinea pigs were used in this experiment. HSV-1 virus stock (0.035 ml) was applied to each zone and introduced through the skin at the well-space area by 10 activity of a six-pronged spring-loaded vaccine device (Sterneedle, Pan Ray Division, Ormont Drug). , Englewood, New Jersey). The inoculation day was day 0. Approximately 250 mg of test drug was applied at 4 × / day on days 1, 2 and 3.

Dosage of Group I by reducing the dosing regimen for 5% ACV / PEG (Zovirax Ointment) to 4x / day for 1, 2 and 3 days in our standard dosing regimen of 5x / day for 1, 2 and 3 days Matched to therapy.

For Group II and Group III, dosing regimens for 5% ACV / PEG (Zovirax Ointment) of our standard dosing regimen at 5x / day for the first, second and third days were used as experimental controls.

On day 4, the site was treated once with Nair in the back of the animal to remove hairs grown on the back of the animal. The animals were then used to count lesions, take pictures of the animals and measure lesion size. Animals were sacrificed and full thickness skin was removed from different areas. A rectangle of skin from each of the treatment areas was placed in 15 mls of tissue culture medium with 2% fetal bovine serum (FBS) in an ice bath. The samples were then homogenized with a Stomacher 80 Biomaster lab blender (Seward Co.). Tissue debris was pelleted by centrifugation and supernatants collected and cooled to −70 ° C. until assayed for infection by plaque formation in VERO 76 cells (kidney, African Green Monkey, ATCC CRL # 1587).

Skin irritation

We tested the following: (1) ADO-1, ADO-2, ADO-3, and ADO-4; (2) 1% VDO99 cream, 3% VDO99 cream, 5% VDO99 cream and placebo thereof; (3) VGO99 Cream (Diclofenac Sodium, 50mg (RA009)), VDO99 Cream (Diclofenacic Acid, Lidocaine Salt 50mg (RA052)), VAO99 Cream (Lidocaine, 50mg (RA001)) and Placebo Cream (For Skin Irritation, Infection Dosing regimens of 1x / day, 2x / day, 4x / day and 5x / day on all 1st, 2nd and 3rd days on unmanned Hartley crossbred albino guinea pigs.

Group I: ADO-1, ADO-2, ADO-3, and ADO-4

The 5x / day dosing regimen was discontinued early because of the lack of ADO-1, -2 and -3 compounds for the test in infected animals.

All compounds (including vehicle) were moderately stimulated in both 2x / day and 4x / day dosing regimens. However, it was decided to use a 4x / day dosing regimen.

Group II: 1% VDO99 Cream, 3% VDO99 Cream, 5% VDO99 Cream and Placebo

All compounds (including placebo) were stimulated from moderate to severe stimuli in three dosing regimens. With the sponsor, we decided to use the most potent compound (5% VDO99) and its placebo (2 × / day dosing regimen). Even in this dosing regimen we recognized that skin irritation caused by 5% VDO99 and its vehicle may interfere with visualizing the lesion to count and measure the lesion on day 4. This proved to be the case.

Group III: VGO99 cream (diclofenac sodium, 5% (RA009)), VDO99 cream (diclofenac acid, lidocaine salt 50mg (RA052)), VAO99 cream (lidocaine, 50mg (RA001)) and placebo cream thereof

VGO 99 cream and VDO99 cream (including its placebo) were stimulated from moderate to severe in three dosing regimens. VAO 99 cream was stimulated mildly at 1 × and 2 × / day and severe at moderate stimulation at 4 × / day (day 1, 2 and 3).

1% VDO99 cream, 3% VDO99 cream, and placebo creams thereof were stimulated from mild to severe in all three dosing regimens. We decided to use a 2x / day dosing regimen. Even in such dosing regimens, the inventors understood that skin irritation caused by the compound and its vehicle is likely to interfere with visualizing the lesion to count and measure the lesion on day 4. This proved to be the case. On day 4, as infected animals, skin irritation prevented the efficacy evaluation:

3/12 drug / placebo cream pair (1% VD099);

6/12 drug / placebo cream pair (3% VD099);

11/12 drug / placebo cream pair (VG0 99);

8/12 drug / placebo cream pair (VD0 99);

7/12 drug / placebo cream pair (VA0 99).

result

Group I

Ten active versus vehicle pairs were tested.

Infection with HSV-1 exacerbated the irritation caused by the active compound (including vehicle) and it was very difficult to find the lesion to count the lesion on Day 4. This often occurs in these models and was difficult to predict. In addition, the stimulation made it very difficult to measure the lesion from the photograph taken on day 4. Because of this difficulty, the number of lesions and the number of comparisons to the total lesion area were reduced and the opportunity for "n" to be large enough to achieve significantness was reduced.

Compounds that can tolerate humans in this model often can be irritating in animals, so skin irritation in this model may not be a predictor of skin irritation in humans.

Table 1 shows the results of the analysis (InStat. V3, GraphPad Software, Inc.), with the remarkable level for the experiment being p ≦ 0.05.

Compared with vehicle (ADO-4), ADO-1 achieved a statistically significant decrease of 26% in the number of lesions and a 47% statistically significant decrease in the total lesion area. It showed a tendency to reduce virus titers.

Compared with vehicle (ADO-4), ADO-2 achieved a statistically significant decrease of 26% in total lesion area and 51% in virus titer. The number of lesions tended to decrease.

Compared with vehicle (ADO-4), ADO-3 achieved a statistically significant decrease of 86% only in virus titers. Since ADO-3 has been shown to be most stimulated in infected animals, the consequences or lack thereof on the number of lesions and on the total lesion area need to be understood in this context.

5% ACV / PEG achieved a significant reduction in the total lesion area when compared to its vehicle. These results for 5% ACV / PEG were not typical for this model and we generally used a 5x / day dosing regimen on the first, second and third days. We typically observed a significant decrease in total lesion area and virus titer, and the results were very similar to ADO-2.

Group II

With 1% VD099, 3% VD099, 5% VD099 and their respective vehicles, the skin of the animal was all stimulated from moderate to severe. In conjunction with the sponsor, in an effort to preserve the material, we used the most potent compound (5% VD099) and its placebo (dose regimen of 2 × / day on days 1, 2 and 3).

Infection with HSV-1 exacerbated the irritation caused by the compounds tested (including vehicles) and made it difficult to find lesions to count lesions on day 4. This sometimes happens in this model. This stimulus also made it very difficult to measure lesions from photographs taken on day four. Because of this difficulty, the number of lesions and the number of comparisons to the total lesion area have decreased, and the chance that "n" is large enough to achieve significantness has decreased.

Table II shows the results of the analysis (InStat. V3, GraphPad Software, Inc.), with a remarkable level for the experiments p ≦ 0.05.

Compared with its placebo, 5% VD099 achieved a statistically significant reduction of 23% in the number of lesions, a 26% statistically significant reduction in the total lesion area, and a 52% statistically significant reduction in virus titer. Achieved.

Compared to its vehicle, 5% ACV / PEG had 10% lesion number; A significant reduction of 33% of total lesion area and 79% of virus titer was achieved. These results for 5% ACV / PEG are typical for this model. In addition, they reflected a general efficacy pattern for true antiviral agents in this model: the reduction in virus titer was greater than the reduction in the total lesion area, which was greater than the reduction in the number of lesions (viral titer> total lesion). Reduced area> reduced number of lesions).

Group III

1% VD099, 3% VD099, VG0 99, VD0 99, VA0 99 and their respective vehicles were all stimulated from mild to severe to animal skin.

Infection with HSV-1 exacerbated the irritation caused by the test compound (including its vehicle) and made it very difficult to observe the lesion for counting it on day 4. This sometimes happens in this model. This stimulus also made it very difficult to measure lesions from photographs taken on day four. Because of this difficulty, the number of lesions and the comparison to total lesion area has decreased, and the chance that "n" achieves remarkable or even large enough to perform statistical tests has decreased.

Table III shows the results of the analysis (InStat. V3, GraphPad Software, Inc.), where the remarkable level for the experiment is p ≦ 0.05.

 The most notable result is that VGO 99 achieved a statistically significant decrease in viral titer of 93% when compared to its placebo cream.

Compared to its vehicle, 5% ACV / PEG achieved a significant reduction of 27% of total lesion area and 71% of virus titer. These results for 5% ACV / PEG were typical for this model. In addition, they reflected the general efficacy pattern observed for true antiviral drugs in this model: the reduction in virus titer is greater than the reduction in the total lesion area, which is greater than the reduction in the number of lesions (viral titer> total lesion area). Decrease> decrease in the number of lesions).

Summary of results

Group I

ADO-3 (5% lidofenac) achieved a 86% reduction in virus titer.

ADO-1 (a combination of acyclovir and lidofenac) did not achieve a reduction in virus titer as well as lidofenac. However, ADO-1 achieved a smaller but significant reduction in lesion count and total lesion area.

Group II

5% VDO99 (RA034) (5% lidofenac) was achieved most mildly, but showed significant results in all three measures of efficacy in this model. Both 5% VDO99 and its vehicles were also equally irritating to the skin of the animals.

Group III

VGO99 (RA009) (diclofenac sodium, 50 mg / g (5% w / w)) achieved a 93% reduction in virus titer in this model. Both VG0 99 and its placebo creams also stimulated the animal's skin equally and prevented the evaluation of the effect of the compound by reducing the number of lesions and the total lesion area. In addition, the results are summarized in FIGS. 1 and 2. 1 shows the inhibitory effects on lesion number, lesion area and viral titer by (a) 5% lidofenac and 5% acyclovir, (b) 5% acyclovir, and (c) 5% lidofenac Indicates. Since there are three data points of 5% lidofenac, the data for 5% lidofenac in the graph represents the mean of three sets of data. 1 shows that 5% acyclovir + 5% lidofenac had the highest inhibitory effect in lesion number and lesion area, and 5% lidofenac showed the highest inhibitory effect in virus titer.

2 compares the inhibitory effects of lidofenac (1%, 3%, and 5%), diclofenac (5%), lidocaine (5%), and acyclovir (5%) on virus titers. Lidofenac (1%, 3%, and 5%) shows the dose response of the inhibitory effect at virus titers. 5% Diclofenac showed a very good inhibitory effect on virus titers. 5% lidocaine had only little inhibitory effect on virus titers.

Table I. ADO-1, -2, -3 vs Veh (ADO-4); And efficacy of 5% ACV / PEG vs. PEG

ADO-1: Acyclovir + Diclofenac Acid Lidocaine Salt.

ADO-2: acyclovir.

ADO-3: Diclofenac acid lidocaine salt.

ADO-4: Vehicle.

1. The percentage difference between the mean lesion severity at the drug-treated site is shown as compared to the vehicle-treated site. Positive values indicate a reduction in lesion severity for the test compound.

2. Day 0 is infection date. All compounds used 4x / day on days 1, 2 and 3. Efficacy measurements were performed on the fourth morning.

3. For statistical analysis, paired data were evaluated by paired t test and the mean of drug and vehicle results was used.

Table II . 5% VD099 (RA034) vs. Veh (RA037); And efficacy of 5% ACV / PEG vs. PEG

5% VD099 (RA034): Diclofenacic acid, lidocaine salt 50 mg / g.

VD099 Placebo Cream (RA037): Vehicle.

1. Shows the percent difference between mean lesion severity at drug-treated sites compared to vehicle-treated sites. Positive values indicate a reduction in lesion severity for the test compound.

2. Day 0 is infection date. 5% VD099 and its vehicle were used at 2 × / day on days 1, 2 and 3. 5% ACV / PEG and PEG were used at 5 × / day on days 1, 2 and 3. Efficacy measurements were taken on the fourth day morning.

3. For statistical analysis, paired data were evaluated by paired t test and the mean of drug and vehicle results was used.

Table III . 1% lidofenac cream (RA032) versus cream placebo; 3% lidofenac cream (RA033) versus cream placebo; 5% Diclofenac Sodium Cream (RA009) vs. Cream Placebo; 5% lidofenac cream (RA052) versus cream placebo; 5% lidocaine cream (RA001) vs. cream placebo; 5% ACV / PEG vs. PEG.

1. Shows the percent difference between mean lesion severity at drug-treated sites compared to vehicle-treated sites. Positive values indicate a reduction in lesion severity for the test compound.

2. Day 0 is infection date. All compounds were used at 2 × / day on days 1, 2 and 3 except 5% ACV / PEG versus PEG. 5% ACV / PEG vs. PEG was used at 5 × / day on days 1, 2 and 3. Efficacy measurements were taken on the fourth day morning.

3. For statistical analysis, paired data were evaluated by paired t test and the mean of drug and vehicle results was used.

4. ND, not performed.

5. NA, not applicable. Too low a value to perform the test.

Example 3. Clinical Research Protocols

purpose:

To evaluate the effectiveness of VGO99 (5% Diclofenac Sodium Cream) in patients with shingles. Efficacy is judged by pain intensity and lesion assessment.

Study end point

Evaluate the following endpoints:

1차 효능 종결점은 대상포진-연계된 통증이 완전히 중지한 시점이다. 환자가 7 일 이상 동안 통증이 없는 경우를 통증의 완전한 중지를 달성한 것으로 규정한다 (통증은 0 ~ 100 의 수적인 규모에서 0 으로 보고됨).

The primary efficacy end point is when the shingles-associated pain completely stopped. Patients who have not had pain for more than 7 days are defined as achieving complete cessation of pain (pain is reported as 0 on a numerical scale of 0-100).

급성 상 통증의 손실 시점 (모든 크러스트가 손실되었을 때의 지점까지 겪은 통증).

The point of loss of acute phase pain (pain up to the point when all the crust is lost).

후속조치 기간의 종결시까지 대상포진-연계된 통증의 완전한 중지를 달성한 환자의 조발생률 (crude rate).

Crude rate of patients who achieved complete cessation of shingles-associated pain by the end of the follow-up period.

후속조치 기간의 종결시 및 치료 기간의 종결시에서 소수포, 궤양 및 크러스트 없는 환자의 조발생률.

Early incidence of patients without vesicles, ulcers and crusts at the end of the follow-up period and at the end of the treatment period.

연구 약제 투여 후 특정 임상 방문 시 VAS 통증 스코어에서 % 감소.

% Reduction in VAS pain score at specific clinical visits after study drug administration.

Treatment regimen : topical VGO99 cream, 10 g / tube, topical use on lesion

Control therapy : topical placebo cream, 10 g / tube, topical use on the lesion

patient

20세~75세의 남성 또는 여성.

Men or women between 20 and 75 years old.

국소적, 피부 병변 (구진, 반 또는 소수포) 에 의한 복잡하지 않은 대상포진의 임상 진단받은 환자.

Patients who have been clinically diagnosed with uncomplicated shingles with local, skin lesions (papillary, semi or vesicular).

연구 약물을, 대상포진으로 인한 발진 및/또는 버드 소수포의 온셋 후 72 시간 이내에 투여될 수 있는 상태의 환자.

Patients in a condition where the study drug can be administered within 72 hours after onset of shingles and / or bud vesicles due to herpes zoster.

가시적 아날로그 스케일 (VAS) 상에서 40 mm 이상의 점수를 가져야만하는 스크리닝/기준선에서의 환자.

Patients at screening / baseline should have a score of 40 mm or greater on visible analog scale (VAS).

프로토콜에서 기술되는 바와 같이 연구 다이어리의 완료를 포함하는 조사관의 지시를 이해하고 따르는 능력.

Ability to understand and follow the investigator's instructions, including the completion of the study diary as described in the protocol.

Test protocol

Patients who meet all selection criteria are randomly appointed to receive one of the following treatments for 28 days:

Group I: VGO99 Cream (5% Diclofenac Sodium)

Group II: Placebo Cream

Patients are randomly selected to receive either 0.05 Vg99 cream or placebo cream about 0.05 g / cm 2, 4 times per day until complete stop of shingles-associated pain (but not more than 28 days). After the last dose of study drug administration, all patients were followed for 4 weeks.

The study lasted about 8 weeks and included seven study visits on Day 0 (baseline), 3 ± 1, 7 ± 1, 14 ± 2, 21 ± 2, 28 ± 2 and 56 ± 7. All study visits included a questionnaire about pain levels and included testing of affected skin areas.

Statistical method

For efficacy endpoints, the Kaplan-Meier method was performed during the time point for filamentous variables (including time to complete stop of shingles-associated pain and time to loss of acute phase pain), 2-sided The median according to the 95% confidence interval was reported. The log-rank test was used to compare these time points in the two groups of topical formulations until the patient's treatment for 28 days or when a particular event was achieved, whichever comes first. Cox regression models were used to analyze event time points, time points from rash onset for treatment initiation, and / or significant diagnostic index time points among treatment groups adjusted for gender.

The invention, methods, and manufacturing processes, and methods of using the same, are now described clearly, decisively, and accurately throughout, to enable one skilled in the art to apply, manufacture, and use the same. It is evident that the above described preferred embodiments of the invention can be modified without departing from the scope of the invention in the claims. In particular, to clear and clarify the subject matter regarded as the present invention, the following claims conclude the specification.

Claims (5)

A method of inhibiting herpes virus activity in a patient, comprising:
Identifying a patient infected with herpes virus, and
Topically administering to the patient an active ingredient consisting essentially of an effective amount of diclofenac or a pharmaceutically acceptable salt thereof,
This inhibits viral activity. The method of claim 1, wherein the herpes virus is selected from the group consisting of herpes simplex virus type-1 (HSV-1), herpes simplex virus type-2, varicella zoster virus, and combinations thereof. The method of claim 1, wherein diclofenac is administered topically to the lesion on the external tissue of the patient. The method of claim 1 wherein the effective amount of diclofenac is about 3-5% (w / w). The method of claim 1 wherein the effective amount of diclofenac is about 5% (w / w).

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